RSK2 in Estrogen Receptor Positive (ER+) Breast Cancer

雌激素受体阳性 (ER) 乳腺癌中的 RSK2

• 批准号: 10207532
• 负责人: Deborah Lannigan
• 金额: $ 36万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207532
• 关键词: Antiestrogen Therapy; Automobile Driving; Biochemical; Biological; Breast; Bypass; Cell Nucleus; Cells; Complex; Crystallography; Cytoplasm; Data; Development; Diabetes Mellitus; Diagnosis; Disease; Drug Design; Drug Kinetics; Ductal Epithelium; Endocrine; Engineering; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen receptor positive; Evaluation; Failure; Generations; Genetic; Genetic Transcription; Growth; In Vitro; Induced Mutation; Intraductal Hyperplasia; Knockout Mice; Lead; Legal patent; Malignant Neoplasms; Mammary gland; Mediating; Metastatic breast cancer; Modeling; Molecular Conformation; Neoplasm Metastasis; Neoplastic Cell Transformation; Nuclear; Parents; Patient-Focused Outcomes; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Population; Process; Proliferating; Property; Protein Kinase; Resistance; Series; Specificity; Structure; Structure-Activity Relationship; Tamoxifen; Testing; Toxic effect; Transgenic Mice; analog; base; breast cancer progression; cardiovascular infection; clinical translation; estrogen disruption; experimental study; genetic signature; hormone therapy; improved; improved outcome; in vitro activity; in vitro testing; in vivo; in vivo Model; inhibitor/antagonist; insight; longitudinal analysis; malignant breast neoplasm; mortality; mouse model; mutant; novel; novel therapeutics; overexpression; patient derived xenograft model; patient response; patient stratification; programs; side effect; statistics; therapy resistant; tumor; tumor growth; tumorigenesis

Endocrine-based therapies have been very effective at reducing mortality but ~ 25% of patients will progress and only 30% of those with metastatic disease will respond. Therefore, there is a tremendous need to identify the mechanisms that drive estrogen receptor alpha positive (ER+) breast cancer and promote invasion. We found that ERα sequesters activated RSK2, a Ser/Thr protein kinase, into the nucleus to promote neoplastic transformation and invasive tumor growth. Anti-estrogens disrupted the RSK2/ERα complex, driving RSK2 into the cytoplasm with corresponding reduced tumor growth. We hypothesize that failure to disrupt the interaction between RSK2 and ERα with endocrine-based therapy leads to metastasis. In support of this hypothesis the RSK2 gene signature stratifies patients with invasive breast cancer based on positivity for ERα. The mechanism by which RSK2 promotes ER+ breast cancer progression will be identified and evaluated in patient-derived xenografts (aim 1). We will test whether RSK2 in complex with a tamoxifen- resistant ERα mutant drives metastasis using engineered ER+ breast lines (aim 2). RSK inhibitors based on the parent compound, SL0101, will be generated to identify compounds with improved in vivo efficacy to inhibit ER+ tumor growth and metastasis (aim 3). Data generated in this proposal will be analyzed using the appropriate statistics for end point and longitudinal analysis. The successful development of a RSK inhibitor could dramatically improve outcomes for patients with ER+ metastatic breast cancer.

基于内分泌的治疗在降低死亡率方面非常有效，但约25%的患者会进展 只有30%的转移性疾病患者会有反应因此，有一个巨大的需要，以确定 驱动雌激素受体α阳性（ER+）乳腺癌和促进侵袭的机制。我们 发现ERα螯合物激活RSK 2（一种Ser/Thr蛋白激酶）进入细胞核，促进肿瘤形成， 转化和侵袭性肿瘤生长。抗雌激素破坏了RSK 2/ERα复合物，驱动RSK 2 进入细胞质，相应地减少肿瘤生长。我们假设如果不能破坏 RSK 2和ERα与基于内分泌的治疗之间的相互作用导致转移。为支持这一 假设RSK 2基因签名基于以下各项的阳性对浸润性乳腺癌患者进行分层： ERα。RSK 2促进ER+乳腺癌进展的机制将被确定， 在患者来源的异种移植物中进行评估（目的1）。我们将测试RSK 2是否与他莫昔芬复合- 耐药ERα突变体使用工程化ER+乳腺细胞系驱动转移（目的2）。RSK抑制剂基于 将产生母体化合物SL 0101，以鉴定具有改善的体内抑制功效的化合物， ER+肿瘤生长和转移（目的3）。本提案中生成的数据将使用 用于终点和纵向分析的适当统计。RSK抑制剂的成功开发 可以显着改善ER+转移性乳腺癌患者的预后。